Imaging of functional (G-protein coupled, in high-affinity state) dopamine receptors has been limited due to a lack of selective imaging agents. At University of California-Irvine (UCI), we have several major programs that would gain from imaging functional dopamine receptors. These include: (a). study of addiction to substance abuse drugs since D3 receptors in the ventral striatum are strongly implicated; (b). study of dopamine release since dopamine competes with a more sensitive PET radiotracer at functional sites; (c). the study of etiology of disease states such as schizophrenia, manic depression and Parkinson's disease where the dopaminergic system is strongly implicated; and (d). study of therapeutic drugs that may selectively affect functional receptors. We have successfully developed a selective fluorine-18 agents, 18F-5-OH-FPPAT and 18F-7-OH-FHXPAT for imaging functional dopamine D2 and D3 receptor. In animal PET studies selective binding of 18F-5-OH-FPPAT and 18F-7-OH-FHXPAT was in the dorsal and ventral striatum with limited binding in the cerebellum. The specific brain region binding and short scan time suggest that 18F-5-OH-FPPAT and 18F- 7-OH-FHXPAT may have good potential as a PET imaging agent for functional receptors in humans. Therefore, our goal in this NIH application is to establish automated radiosynthesis chemistry, manufacturing and control procedures for 18F-5-OH-FPPAT and 18F-7-OH-FHXPAT. This will be followed by PET studies to establish in vivo quantitation methods which will be applied to chronic effects of substance abuse drugs (methamphetamine, cocaine, alcohol and nicotine). Autoradiographic studies on postmortem human brain tissue will be carried out with 18F-5-OH-FPPAT and 18F-7-OH-FHXPAT to evaluate diagnostic use. The overall proposed research in this application will thus support investigations in several brain disorders involving anomalies in the function of dopamine receptors.